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- PDB-4twp: The crystal structure of human abl1 T315I gatekeeper mutant kinas... -

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Basic information

Entry
Database: PDB / ID: 4twp
TitleThe crystal structure of human abl1 T315I gatekeeper mutant kinase domain in complex with axitinib
ComponentsTyrosine-protein kinase ABL1
KeywordsTransferase/Transferase Inhibitor / gatekeeper mutant Kinase domain DFGin / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / protein localization to cytoplasmic microtubule plus-end / DN4 thymocyte differentiation / DNA conformation change / response to epinephrine / activation of protein kinase C activity / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process / delta-catenin binding ...positive regulation of actin filament binding / negative regulation of ubiquitin-protein transferase activity / protein localization to cytoplasmic microtubule plus-end / DN4 thymocyte differentiation / DNA conformation change / response to epinephrine / activation of protein kinase C activity / phospholipase C-inhibiting G protein-coupled receptor signaling pathway / podocyte apoptotic process / delta-catenin binding / Role of ABL in ROBO-SLIT signaling / transitional one stage B cell differentiation / regulation of postsynaptic specialization assembly / regulation of modification of synaptic structure / nicotinate-nucleotide adenylyltransferase activity / cerebellum morphogenesis / neuroepithelial cell differentiation / B cell proliferation involved in immune response / : / positive regulation of Wnt signaling pathway, planar cell polarity pathway / positive regulation of extracellular matrix organization / microspike assembly / B-1 B cell homeostasis / neuropilin signaling pathway / neuropilin binding / mitochondrial depolarization / bubble DNA binding / regulation of cell motility / positive regulation of establishment of T cell polarity / activated T cell proliferation / cellular response to dopamine / myoblast proliferation / positive regulation of blood vessel branching / proline-rich region binding / syntaxin binding / regulation of Cdc42 protein signal transduction / mitogen-activated protein kinase binding / regulation of hematopoietic stem cell differentiation / alpha-beta T cell differentiation / positive regulation of cell migration involved in sprouting angiogenesis / positive regulation of dendrite development / regulation of axon extension / regulation of T cell differentiation / positive regulation of peptidyl-tyrosine phosphorylation / cardiac muscle cell proliferation / negative regulation of cell-cell adhesion / HDR through Single Strand Annealing (SSA) / positive regulation of osteoblast proliferation / Myogenesis / platelet-derived growth factor receptor-beta signaling pathway / RUNX2 regulates osteoblast differentiation / regulation of microtubule polymerization / Fc-gamma receptor signaling pathway involved in phagocytosis / Bergmann glial cell differentiation / vascular endothelial cell response to oscillatory fluid shear stress / regulation of endocytosis / associative learning / negative regulation of cellular senescence / negative regulation of long-term synaptic potentiation / neuromuscular process controlling balance / negative regulation of mitotic cell cycle / actin monomer binding / signal transduction in response to DNA damage / negative regulation of BMP signaling pathway / positive regulation of focal adhesion assembly / peptidyl-tyrosine autophosphorylation / RHO GTPases Activate WASPs and WAVEs / canonical NF-kappaB signal transduction / BMP signaling pathway / ephrin receptor signaling pathway / positive regulation of T cell migration / endothelial cell migration / negative regulation of double-strand break repair via homologous recombination / cellular response to transforming growth factor beta stimulus / negative regulation of endothelial cell apoptotic process / mismatch repair / regulation of cell adhesion / positive regulation of vasoconstriction / four-way junction DNA binding / spleen development / positive regulation of stress fiber assembly / ephrin receptor binding / ruffle / ERK1 and ERK2 cascade / actin filament polymerization / phosphotyrosine residue binding / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of endothelial cell migration / positive regulation of interleukin-2 production / substrate adhesion-dependent cell spreading / positive regulation of mitotic cell cycle / SH2 domain binding / protein kinase C binding / response to endoplasmic reticulum stress / positive regulation of release of sequestered calcium ion into cytosol / thymus development / Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells / integrin-mediated signaling pathway / post-embryonic development / B cell receptor signaling pathway
Similarity search - Function
F-actin binding / F-actin binding / F-actin binding domain (FABD) / Tyrosine-protein kinase ABL, SH2 domain / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain ...F-actin binding / F-actin binding / F-actin binding domain (FABD) / Tyrosine-protein kinase ABL, SH2 domain / : / SH3 domain / SH2 domain / Src homology 2 (SH2) domain profile. / Src homology 2 domains / SH2 domain / Src homology 3 domains / SH2 domain superfamily / SH3-like domain superfamily / Src homology 3 (SH3) domain profile. / SH3 domain / Tyrosine-protein kinase, catalytic domain / Tyrosine kinase, catalytic domain / Tyrosine protein kinases specific active-site signature. / Tyrosine-protein kinase, active site / Serine-threonine/tyrosine-protein kinase, catalytic domain / Protein tyrosine and serine/threonine kinase / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
AXITINIB / NICKEL (II) ION / Tyrosine-protein kinase ABL1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsJohnson, E. / McTigue, M. / Cronin, C.N.
CitationJournal: Nature / Year: 2015
Title: Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation.
Authors: Pemovska, T. / Johnson, E. / Kontro, M. / Repasky, G.A. / Chen, J. / Wells, P. / Cronin, C.N. / McTigue, M. / Kallioniemi, O. / Porkka, K. / Murray, B.W. / Wennerberg, K.
History
DepositionJul 1, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 11, 2015Provider: repository / Type: Initial release
Revision 1.1Mar 4, 2015Group: Database references
Revision 1.2Mar 18, 2015Group: Database references
Revision 1.3May 13, 2015Group: Database references
Revision 1.4Nov 22, 2017Group: Derived calculations / Refinement description / Source and taxonomy
Category: entity_src_gen / pdbx_struct_oper_list / software
Item: _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation
Revision 1.5Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id
Revision 1.6Aug 7, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond
Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 ..._chem_comp_atom.atom_id / _chem_comp_bond.atom_id_1 / _chem_comp_bond.atom_id_2 / _chem_comp_bond.value_order

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Tyrosine-protein kinase ABL1
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)63,91111
Polymers62,8342
Non-polymers1,0779
Water3,405189
1
A: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9676
Polymers31,4171
Non-polymers5505
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Tyrosine-protein kinase ABL1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,9445
Polymers31,4171
Non-polymers5274
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.818, 113.801, 131.164
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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Components

#1: Protein Tyrosine-protein kinase ABL1 / Abelson murine leukemia viral oncogene homolog 1 / Abelson tyrosine-protein kinase 1 / Proto- ...Abelson murine leukemia viral oncogene homolog 1 / Abelson tyrosine-protein kinase 1 / Proto-oncogene c-Abl / p150


Mass: 31417.045 Da / Num. of mol.: 2 / Fragment: UNP residues 252-522 / Mutation: T315I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ABL1, ABL, JTK7 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P00519, non-specific protein-tyrosine kinase
#2: Chemical ChemComp-AXI / AXITINIB / N-METHYL-2-(3-((E)-2-PYRIDIN-2-YL-VINYL)-1H-INDAZOL-6-YLSULFANYL)-BENZAMIDE


Mass: 386.470 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C22H18N4OS / Comment: inhibitor*YM
#3: Chemical
ChemComp-NI / NICKEL (II) ION


Mass: 58.693 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Ni
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 189 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 3.37 Å3/Da / Density % sol: 63.55 %
Crystal growTemperature: 286.15 K / Method: vapor diffusion, sitting drop / pH: 7
Details: 0.1 M HEPES (pH 7.00) 15.0 %w/v PEG 3350 0.01 M Magnesium chloride hexahydrate 0.0050 M Nickel(II) chloride hexahydrate 5.0 %v/v Glycerol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 27, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.4→85.957 Å / Num. obs: 34049 / % possible obs: 99.9 % / Redundancy: 6.5 % / Biso Wilson estimate: 49.26 Å2 / Rpim(I) all: 0.026 / Rrim(I) all: 0.066 / Rsym value: 0.055 / Net I/av σ(I): 12.167 / Net I/σ(I): 22.7 / Num. measured all: 220382
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2.4-2.536.80.6241.23336248950.2770.6243.3100
2.53-2.686.70.4241.63090146280.190.4245100
2.68-2.876.40.24332810943690.1130.2437.9100
2.87-3.16.70.1395.22732441050.0620.13912.9100
3.1-3.396.70.0819.12525037570.0360.08120.8100
3.39-3.7960.05213.82043134210.0270.05230.499.7
3.79-4.386.30.03122.71914930280.0150.03146.499.3
4.38-5.376.30.02725.41617425830.0130.0275399.9
5.37-7.596.30.02427.61291620560.0120.02451.699.9
7.59-65.5825.60.01731.8676612070.0090.01767.399.3

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.7.1_743)refinement
SCALA3.3.20data scaling
Cootmodel building
PHASERphasing
PDB_EXTRACT3.14data extraction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→52.137 Å / FOM work R set: 0.8299 / SU ML: 0.69 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 23.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2414 1681 4.95 %Random
Rwork0.2117 32286 --
obs0.2132 33967 99.7 %-
Solvent computationShrinkage radii: 0.83 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 43.952 Å2 / ksol: 0.333 e/Å3
Displacement parametersBiso max: 143.29 Å2 / Biso mean: 58.02 Å2 / Biso min: 25.18 Å2
Baniso -1Baniso -2Baniso -3
1--7.8556 Å20 Å20 Å2
2--5.4575 Å20 Å2
3---2.3981 Å2
Refinement stepCycle: final / Resolution: 2.4→52.137 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4365 0 63 189 4617
Biso mean--55.69 50.65 -
Num. residues----537
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0094538
X-RAY DIFFRACTIONf_angle_d1.1266141
X-RAY DIFFRACTIONf_chiral_restr0.079646
X-RAY DIFFRACTIONf_plane_restr0.005774
X-RAY DIFFRACTIONf_dihedral_angle_d16.5541679
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 12

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.4-2.47060.35861340.27726802814100
2.4706-2.55040.30551290.279226322761100
2.5504-2.64150.3021300.266126632793100
2.6415-2.74730.31521440.261226502794100
2.7473-2.87230.30441430.243726652808100
2.8723-3.02370.25151490.22926482797100
3.0237-3.21310.27781440.227526822826100
3.2131-3.46120.23261380.215626712809100
3.4612-3.80940.24541450.20892688283399
3.8094-4.36040.20541320.1862700283299
4.3604-5.49270.19821400.177527382878100
5.4927-52.14880.22571530.20672869302299

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